I propose a novel approach to the study of the mechanism of autoimmunization. The recent production of hybridomas that synthesize anti-DNA autoantibodies that are characteristic of systemic lupus erythematosus makes this new approach possible. Hybridoma mRNA will be used to clone the VH genes expressed in these autoantibodies. These cloned DNA probes will be used to determine whether autoantibodies are encoded in the germ-line of "autoimmune" strains of mice or whether they arise by extensive somatic mutation (mutant clone theory). If extensive somatic mutation is involved, this will suggest new directions for research in autoimmune disease. If the expressed autoimmune VH region is encoded in the germ-line DNA of "autoimmune" mice, then we will determine whether it is also present in the germ-line DNA of normal mice. The presence of this VH gene in the germ-line of normal and autoimmune mice would be strong evidence that autoimmune disease results from an immunoregulatory defect. Based on recent observations with other cloned VH genes, we expect to find a family of related VH genes in germ-line DNA. The most related member of the family will be cloned in order to compare its sequence to that of the VH gene expressed in the autoantibody. Thus, these experiments, in addition to their relevance to autoimmune disease, will also provide information on the number, relatedness and conservation of VH gene families in different mice strains.